Determinants of drug effects in preclinical assays of pain-related behavioral depression: Considerations for analgesic drug development.

Pain-related behavioral depression is a cardinal sign of pain diagnosis and a target of pain treatment in both human and veterinary medicine. As such, pain-related behavioral depression can serve as class of translational endpoints in research on the expression, mechanisms, and treatment of pain, and prevailing evidence suggests that use of these endpoints can increase the accuracy of preclinical-to-clinical translation in analgesic drug discovery. In assays of pain-depressed behavior, a behavioral endpoint is selected that occurs at a high and reliable rate under baseline conditions and is depressed to lower levels after delivery of a noxious stimulus. Drugs are then evaluated for their effectiveness to rescue expression of the pain-depressed behavior. Net drug effects in these procedures reflect the integration of 2 general components: (1) analgesic effects that reduce sensory sensitivity to the noxious stimulus to increase expression of the target behavior and (2) nonanalgesic motor/cognitive effects that can both reduce behavior when the drug is administered alone and oppose expression of analgesic effects when the drug is administered in the context of a pain state. Drug effects can be further modulated by factors that include (1) the noxious stimulus type and intensity, (2) the target behavior depressed by that noxious stimulus, and (3) the genotype and individual history of the subject to which the noxious stimulus is delivered and by which the target behavior is emitted. Improved appreciation of factors that modulate drug effects on pain-depressed behavior could improve the utility of these procedures in analgesic drug discovery. SIGNIFICANCE STATEMENT: Preclinical procedures that evaluate drug effects on pain-related behavioral depression can improve preclinical-to-clinical translation of drug effects in analgesic drug discovery. This article reviews some of the determinants of drug effects in these procedures.